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Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA

  • Yanghao Hou
  • Jorge Pinheiro
  • Felix Sahm
  • David E. Reuss
  • Daniel Schrimpf
  • Damian Stichel
  • Belén Casalini
  • Christian Koelsche
  • Philipp Sievers
  • Annika K. Wefers
  • Annekathrin Reinhardt
  • Azadeh Ebrahimi
  • Francisco Fernández-Klett
  • Stefan Pusch
  • Jochen Meier
  • Leonille Schweizer
  • Werner Paulus
  • Marco Prinz
  • Christian Hartmann
  • Karl H. Plate
  • Guido Reifenberger
  • Torsten Pietsch
  • Pascale Varlet
  • Mélanie Pagès
  • Ulrich Schüller
  • David Scheie
  • Karin de Stricker
  • Stephan Frank
  • Jürgen Hench
  • Bianca Pollo
  • Sebastian Brandner
  • Andreas Unterberg
  • Stefan M. Pfister
  • David T. W. Jones
  • Andrey Korshunov
  • Wolfgang Wick
  • David Capper
  • Ingmar Blümcke
  • Andreas von DeimlingEmail author
  • Luca Bertero
Original Paper

Abstract

Papillary glioneuronal tumor (PGNT) is a WHO-defined brain tumor entity that poses a major diagnostic challenge. Recently, SLC44A1PRKCA fusions have been described in PGNT. We subjected 28 brain tumors from different institutions histologically diagnosed as PGNT to molecular and morphological analysis. Array-based methylation analysis revealed that 17/28 tumors exhibited methylation profiles typical for other tumor entities, mostly dysembryoplastic neuroepithelial tumor and hemispheric pilocytic astrocytoma. Conversely, 11/28 tumors exhibited a unique profile, thus constituting a distinct methylation class PGNT. By screening the extended Heidelberg cohort containing over 25,000 CNS tumors, we identified three additional tumors belonging to this methylation cluster but originally histologically diagnosed otherwise. RNA sequencing for the detection of SLC44A1PRKCA fusions could be performed on 19 of the tumors, 10 of them belonging to the methylation class PGNT. In two additional cases, SLC44A1PRKCA fusions were confirmed by FISH. We detected fusions involving PRKCA in all cases of this methylation class with material available for analyses: the canonical SLC44A1PRKCA fusion was observed in 11/12 tumors, while the remaining case exhibited a NOTCH1-PRKCA fusion. Neither of the fusions was found in the tumors belonging to other methylation classes. Our results point towards a high misclassification rate of the morphological diagnosis PGNT and clearly demonstrate the necessity of molecular analyses. PRKCA fusions are highly diagnostic for PGNT, and detection by RNA sequencing enables the identification of rare fusion partners. Methylation analysis recognizes a unique methylation class PGNT irrespective of the nature of the PRKCA fusion.

Keywords

Papillary glioneuronal tumor SLC44A1 PRKCA NOTCH1 DNA methylation RNA sequencing 

Notes

Acknowledgements

We thank V. Zeller, U. Vogel, H. Y. Nguyen, L. Dörner, U. Lass, A. Habel, K. Lindenberg, S. Kocher, and R. Quan for their extraordinary technical support, and the microarray unit of the DKFZ Genomics and Proteomics Core Facility for Illumina DNA methylation array analysis support. This study was partly supported by the Else Kröner-Fresenius Stiftung (2107_EKES.24) and the Molecular Neuropathology 2.0 study funded by the Deutsche Kinderkrebsstiftung. U.S. is supported by the Fördergemeinschaft Kinderkrebszentrum Hamburg. Part of the study was funded by the National Institute for Health Research to UCLH Biomedical Research Centre (BRC399/NS/RB/101410). Sebastian Brandner is also supported by the Department of Health’s NIHR Biomedical Research Centre’s funding scheme.

Supplementary material

401_2019_1969_MOESM1_ESM.tif (32.4 mb)
Supplementary Material 1 Unsupervised hierarchical clustering of the overall cohort of cases (n = 31) plus reference cases (n = 130). PGNT: histological defined papillary glioneuronal tumors; RGNT: MC rosette-forming glioneuronal tumor; DNT: MC dysembryoplastic neuroepithelial tumor; PA MID: MC midline pilocytic astrocytoma; PA PF: MC posterior fossa pilocytic astrocytoma; DLGNT: MC diffuse leptomeningeal glioneuronal tumor; CN: MC central neurocytoma; EP RELA: MC ependymoma RELA fused; PXA: MC pleomorphic xanthoastrocytoma; LGG MYB: MC low-grade glioma, MYB/MYBL1; PA HEMI: MC hemispheric pilocytic astrocytoma; NORM HEMI: MC normal hemispheric cortex; GG: MC ganglioglioma; CG: MC chordoid glioma of the third ventricle (TIFF 33,182 kb)
401_2019_1969_MOESM2_ESM.docx (20 kb)
Supplementary Material 2 Clinical and molecular characteristics of the whole cohort (n = 31). *Identified tumors in large t-SNE plot belonging to MC PGNT, but originally histologically diagnosed otherwise (DOCX 20 kb)
401_2019_1969_MOESM3_ESM.tif (8.8 mb)
Supplementary Material 3 Fisher’s exact test showing a significant association between MC PGNT and presence of fusions involving PRKCA (p < 0.0001). (TIFF 9000 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Yanghao Hou
    • 1
  • Jorge Pinheiro
    • 2
  • Felix Sahm
    • 1
    • 3
    • 4
  • David E. Reuss
    • 1
    • 3
  • Daniel Schrimpf
    • 1
    • 3
  • Damian Stichel
    • 1
    • 3
  • Belén Casalini
    • 1
    • 3
  • Christian Koelsche
    • 5
  • Philipp Sievers
    • 1
    • 3
  • Annika K. Wefers
    • 1
    • 3
  • Annekathrin Reinhardt
    • 1
    • 3
  • Azadeh Ebrahimi
    • 1
    • 3
  • Francisco Fernández-Klett
    • 1
    • 3
  • Stefan Pusch
    • 1
    • 3
  • Jochen Meier
    • 1
  • Leonille Schweizer
    • 6
    • 7
  • Werner Paulus
    • 8
  • Marco Prinz
    • 9
    • 10
    • 11
  • Christian Hartmann
    • 12
  • Karl H. Plate
    • 13
    • 14
  • Guido Reifenberger
    • 15
  • Torsten Pietsch
    • 16
  • Pascale Varlet
    • 17
  • Mélanie Pagès
    • 17
  • Ulrich Schüller
    • 18
    • 19
    • 20
  • David Scheie
    • 21
  • Karin de Stricker
    • 21
  • Stephan Frank
    • 22
  • Jürgen Hench
    • 22
  • Bianca Pollo
    • 23
  • Sebastian Brandner
    • 24
  • Andreas Unterberg
    • 25
  • Stefan M. Pfister
    • 4
    • 26
    • 27
  • David T. W. Jones
    • 4
    • 28
  • Andrey Korshunov
    • 1
    • 3
    • 4
  • Wolfgang Wick
    • 3
    • 29
  • David Capper
    • 6
    • 7
  • Ingmar Blümcke
    • 30
  • Andreas von Deimling
    • 1
    • 3
    Email author
  • Luca Bertero
    • 1
    • 31
  1. 1.Department of Neuropathology, Institute of PathologyUniversity Hospital HeidelbergHeidelbergGermany
  2. 2.Department of PathologyCentro Hospitalar São JoãoPortoPortugal
  3. 3.Clinical Cooperation Unit NeuropathologyGerman Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.Hopp Children’s Cancer Center Heidelberg (KiTZ)HeidelbergGermany
  5. 5.Department of General Pathology, Institute of PathologyUniversity Hospital HeidelbergHeidelbergGermany
  6. 6.Department of NeuropathologyCharité, Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin, and Humboldt-Universität Zu Berlin, Berlin Institute of HealthBerlinGermany
  7. 7.German Cancer Consortium (DKTK),Partner Site Berlin,German Cancer Research Center (DKFZ)HeidelbergGermany
  8. 8.Institute of NeuropathologyUniversity Hospital MünsterMünsterGermany
  9. 9.Institute of Neuropathology, Medical FacultyUniversity of FreiburgFreiburgGermany
  10. 10.BIOSS Centre for Biological Signalling StudiesUniversity of FreiburgFreiburgGermany
  11. 11.CIBSS Centre for Integrative Biological Signalling StudiesUniversity of FreiburgFreiburgGermany
  12. 12.Department of NeuropathologyMedizinische Hochschule HannoverHannoverGermany
  13. 13.Department of NeuropathologyUniversity Hospital FrankfurtFrankfurtGermany
  14. 14.German Cancer Consortium (DKTK), Partner Site,Frankfurt/Mainz, German Cancer Research Center(DKFZ)HeidelbergGermany
  15. 15.Department of NeuropathologyUniversity Hospital DüsseldorfDüsseldorfGermany
  16. 16.Department of NeuropathologyUniversity of BonnBonnGermany
  17. 17.Department of Neuropathology, Hôpital Sainte-AnneUniversité Paris V Descartes, Sorbonne Paris CitéParisFrance
  18. 18.Department of NeuropathologyUniversity Hospital Hamburg-EppendorfHamburgGermany
  19. 19.Department of Pediatric Hematology and OncologyUniversity Medical Center Hamburg EppendorfHamburgGermany
  20. 20.Research Institute Children’s Cancer Center HamburgHamburgGermany
  21. 21.Department of PathologyRigshospitaletCopenhagenDenmark
  22. 22.Division of Neuropathology, Department of Medical Genetics and PathologyUniversity Hospital BaselBaselSwitzerland
  23. 23.Department of NeuropathologyNeurological Institute BestaMilanItaly
  24. 24.Division of NeuropathologyThe National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, and, Department of Neurodegenerative Disease, UCL Queen Square Institute of NeurologyLondonUK
  25. 25.Division of Experimental Neurosurgery, Department of NeurosurgeryUniversity Hospital HeidelbergHeidelbergGermany
  26. 26.Division of Pediatric NeurooncologyGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  27. 27.Department of Pediatric Oncology, Hematology, Immunology and PulmonologyUniversity Hospital HeidelbergHeidelbergGermany
  28. 28.Pediatric Glioma Research GroupGerman Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  29. 29.Department of NeurologyUniversity Hospital HeidelbergHeidelbergGermany
  30. 30.Department of NeuropathologyUniversity Hospital ErlangenErlangenGermany
  31. 31.Pathology Unit, Department of Medical SciencesUniversity of TurinTurinItaly

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